Abstract Chronic back pain related to intervertebral disc (IVD) degeneration is a significant problem, costing billions in the U.S. alone. Despite the staggering disease burden, there is no current effective treatment to retard IVD degeneration and reduce pain because the etiology of IVD degeneration remains unclear. Our preliminary data now indicate that ADAM8 (A Disintegrin And Metalloproteinase 8) is a key enzyme in the degenerative cascade in IVD tissues and represents a major, novel and potentially far-reaching step ahead in understanding disease etiology. Specifically, we have found that ADAM8 acts as a fibronectin- cleaving enzyme in the human IVD. Cleavage of fibronectin and production of pathogenic fragments in the IVD accelerates IVD degeneration. However, several mechanistic aspects remain unclear, including what triggers ADAM8 production and activation, and how the extracellular matrix degradation pathway might be interrupted. Our overall hypothesis is that excessive ADAM8 proteolytic activity results in excessive fibronectin cleavage and subsequent IVD degeneration, and that inhibition of ADAM8 could represent a therapeutic tool to delay or even stop the degenerative cascade in the IVD. To test this novel hypothesis, the following two specific aims are proposed in this pilot study. In Aim 1, we hypothesize that gene inactivation of ADAM8 will protect against IVD degeneration induced by injury. To test this hypothesis, a mouse line that harbors a point mutation in the proteolytic domain (ADAM8E330Q/E330Q) will be used. Coccygeal IVDs will be injured with a needle in mutant and in wild type mice, and we expect to observe reduced IVD degeneration in ADAM8 inactivation mice. MMP (matrix metalloproteinase) inhibitors that inhibit ADAM8 activities will also be tested in this aim. In Aim 2, we will determine whether loss of ADAM8 proteolytic function ameliorates naturally occurring IVD degeneration. This study is innovative in that it will establish a novel biological mechanism of IVD degeneration. Specifically, the study is expected to uncover novel roles of ADAM8 in the degenerative cascade, including activation of fibronectin fragmentation and stimulation of extracellular matrix remodeling in IVDs. ADAM8 has recently been recognized as an attractive target for drug discovery due to its role in cancer and inflammation. Drugs discovered in these fields may be repurposed to treat IVD degeneration. We anticipate that this project will lead to novel IVD therapies that could impact clinical practice. Discoveries of drugs that slow down IVD degeneration would result in a paradigm shift from current invasive surgeries on late stage disease to early interventions and less invasive therapies.